Throughout this application various publications are referred to in brackets. Full citations for these references may be found at the end of the specification. The disclosures of these publications are hereby incorporated by reference in their entirety into the subject application to more fully describe the art to which the subject invention pertains.
The current widespread use of radioactive materials has resulted in the realization of serious and dangerous effects of radiation exposure. As evidenced by the Chernobyl nuclear disaster of 1986 and more recently with the massive radiation leak at the Fukushima I power plant, massive unforeseen radiation exposure is a possibility that must be planned for and mitigated. This is further necessitated by the risk of nuclear warfare or the utilization of a “dirty bomb” by terrorists. Major strides have been made in minimizing the effects of planned radiation exposure, especially in radiology and radiotherapy. Radio-protectors have been developed which have shown efficacy in animal and human studies, and one of these radio-protectors, amifostine, is already in clinical use [1-3]. However, amifostine is limited by its route of administration and toxicity, which would minimize its usefulness in the event of an imminent nuclear disaster. Therefore, there is an unmet need in the development of effective mitigators of radioactive damage.
Acute radiation syndrome (ARS) is an acute illness caused by rapid exposure of most or all of the body to a high dose of penetrating radiation. Its major cause is the depletion of immature parenchymal stem cells in specific tissues. The gastrointestinal (GI) syndrome, one of the three classic ARS syndromes, contributes significantly to early mortality and several debilitating complications that follow severe acute radiation exposure. Occurrence of the GI syndrome is associated with extremely low survival: destructive and irreparable changes occur in the GI tract with loss of intestinal crypts and breakdown of the mucosal barrier. At higher radiation doses, the mortality rate of the gastrointestinal syndrome exceeds that of the hematopoietic syndrome with most victims dying within 2 weeks [4,5].
Milk fat globule-EGF factor 8 (MFG-E8) is a secreted integrin-binding glycoprotein that was first identified as one of the major proteins associated with the milk fat globule membrane in the mouse mammary epithelium [6]. MFG-E8 is widely expressed in different species [7,8]. The human homolog contains 387 amino acids and has been identified by several other names including Lactadherin, SED1 and BA46. Mouse MFG-E8 consists of two-repeated EGF-like domains, a mucin-like domain, and two-repeated discoidin-like domains (C-domains); it contains an integrin-binding motif (RGD sequence) and is reported to have two splice variants. A longer splice variant is expressed in a lactation-dependent manner in mammary tissues while the shorter splice variant is expressed ubiquitously in many tissues. MFG-E8 is a potent opsonin for the clearance of apoptotic cells. It is produced by mononuclear cells of immune-competent organs including the spleen and the liver. MFG-E8 is known to participate in a wide variety of cellular interactions, including phagocytosis of apoptotic cells, adhesion between sperm and the egg coat, repair of intestinal mucosa, mammary gland branching morphogenesis and angiogenesis [8-11].
Increasing danger of nuclear attacks, accidents and potential terrorism has caused major concern towards radiation exposure, and development of therapies for radiation mitigation is of significant value. Gastrointestinal injuries due to radiation exposure cause high mortality, and intestinal crypt cells are extremely sensitive to radiation. Cell proliferation, differentiation, and migration are crucial events required for the maintenance of an intact epithelial layer. MFG-E8 plays an important role in the maintenance of intestinal epithelial homeostasis and the promotion of mucosal healing [7,12-14], which are essential attributes in mitigation of GI impairment after ionizing radiation.
The present invention addresses the need for treatment and prevention of adverse effects of radiation exposure using MFG-E8.